Injected Eye, Fellow Eye and Systemic Pharmacokinetic Modeling of Intravitreally Administered Bevacizumab

Area of Science:

• Pharmacology
• Ocular Drug Delivery
• Pharmacokinetics

Background:

• Simulating retinal drug concentrations after intravitreal administration is challenging due to gaps in ocular physiology knowledge.
• Current models often treat the eye as isolated, neglecting crucial blood-ocular barrier dynamics for systemic data-based predictions.
• Understanding drug disposition across the blood-ocular barrier is vital for accurate ocular drug exposure assessment.

Purpose of the Study:

• To investigate large molecule disposition in the rabbit eye, systemic circulation, and fellow eye using bevacizumab.
• To identify knowledge gaps in physiological processes governing ocular drug distribution.
• To determine key model parameters for eye-plasma drug exchange.

Main Methods:

• Developed a semimechanistic ocular compartmental model for bevacizumab disposition in rabbits.
• Utilized literature data and refined model parameters, including retinal volume and retinal pigment epithelium permeability.
• Incorporated fellow eye observations and plasma-to-aqueous humor backflow to enhance model accuracy.

Main Results:

• The refined model accurately simulated bevacizumab concentrations in the injected eye, plasma, and fellow eye.
• Estimated retinal volume fraction accessible for bevacizumab at 41% and RPE permeability at 5.9 × 10⁻⁹ cm·s⁻¹.
• Introduced a plasma-to-aqueous humor backflow parameter improving fellow eye aqueous humor concentration predictions.

Conclusions:

• The developed model enhances understanding of ocular pharmacokinetics within a systemic context.
• Provides a more physiologically relevant representation of the retinal compartment and blood-ocular barrier processes.
• Offers improved predictions for intravitreal drug concentrations, aiding future ocular drug development.